The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity

Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla 92037, CA, USA. Electronic address: .
Cancer cell (Impact Factor: 23.89). 03/2013; 23(3):332-46. DOI: 10.1016/j.ccr.2013.02.016
Source: PubMed

ABSTRACT Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.

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Available from: William Placzek, Feb 10, 2014
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    • "The normal prostatic epithelial PrEC cells were purchased from Lonza (Allendale, NJ). The human PCa cell lines C4-2, ARCaP E and ARCaP M were established by our laboratory [13e15], and the murine prostate cancer cell line MPC3 was kindly provided by Dr. Neil Bhowmick (Cedars-Sinai Medical Center, Los Angeles, CA) [16]. For hypoxia treatment , cells were grown in a hypoxic chamber (1% O 2 , 5% CO 2 ). "
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    • "Our inability to detect binding of endogenous NCoR1 to CREB in the absence of crosslinking may reflect the short duration of this interaction at steady state. Further studies are needed to examine how different physiological conditions impact the NCoR1/CREB complex and how Siah2 achieves specificity for the removal of NCoR1 in a subset of genes, a phenomenon that was recently exemplified by the role of this E3 ligase in gene-selective androgen receptor regulation (Qi et al., 2013). As an adaptor molecule, NCoR1 is involved in HDAC recruitment (You et al., 2013) and other mechanisms of transcriptional control (Zhou et al., 2008). "
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